Lithium Hydroxide → 4-((2-(Ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol

HRID 1620273Notes

Reaction equation

HRID 1620273 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[C:27]([F:34])[CH:26]=2.[Li+].[OH-]>C1COCC1>[CH2:36]([NH:35][C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][C:27]([F:34])=[C:28]([O:32][CH3:33])[CH:29]=2)[N:24]=1)[CH3:37]

Participants

5

Reactant 3

HCID 3939Lithium HydroxideHCID 68182173HCID 68182173, compound2×HCID 178440211HCID 178440211, compound2×

Product 1

HCID 1784402324-((2-(Ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
155 °C

Procedure

To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (184 mg, 0.744 mmol) in THF (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-7-fluoro-6-methoxyquinolin-2-amine hydrochloride SMA 44096 (227 mg, 0.744 mmol) at RT followed by a 2 N aq. LiOH solution (0.75 mL, 1.50 mmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. The microwave vial was then cooled in an ice bath and the solid was filtered, washed with cold THF (20 mL) and taken up in CH2Cl2:MeOH=9:1 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) gave 83 mg of 4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (5 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 70 as a yellow solid (96 mg, 23% yield).

Workup

  1. temperatureThe microwave vial was then cooled in an ice bath
  2. filtrationthe solid was filtered
  3. washwashed with cold THF (20 mL)
  4. washThe organic solution was washed with brine (10 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated at 40° C. under vacuum
  8. customPurification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5)
  9. customfollowed by a second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5)

Sources & evidence

ORD record
ord-f0d0b17b72034d7ea48efa9dd377c2b9
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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